Roles of Interleukin-17 in Endothelial Cells Endothelial cell (EC) activation and inflammation significantly contribute to vascular inflammation. In addition to being stimulated by proinflammatory/proatherogenic risk factors such as hyperlipidemia, ECs are also the target of proinflammatory cytokines. Since 2003, a new lineage of CD4+RORt+ (retinoid-related orphan receptor) T cells has been defined by its production of proinflammatory cytokine interleukin-17 (IL-17) and hence named T-helper 17 (Th17) cells. These cells are found to play an essential role in promoting autoimmune diseases and inflammation. However, an important question of whether molecular signaling pathway of IL-17 plays a critical role in EC activation remains to be answered. Therefore, the goal of this proposal is to examine a central hypothesis that IL-17, induced by hyperlipidemia, plays a critical role in EC activation. The publications from our labs and others'as well as our preliminary data support this hypothesis: (i) IL-17 receptor A (IL-17RA) is expressed in aortic ECs. High levels of IL-17 receptor C (IL-17RC) expression are observed in ECs, suggesting the functional receptor complex IL-17RA/C is expressed in ECs and is able to initiate signaling in response to IL-17 stimulation;(ii) IL-17 is upregulated in human aortic ECs exposed to disturbed blood flow, an EC activation condition, suggesting that ECs can be further stimulated by IL-17 via an autocrine mechanism;(iii) Plasma IL-17 level and Th17 cells are elevated in apolipoprotein E deficient (ApoE-/- ) atherogenic mice, suggesting that hyperlipidemia makes more IL-17 available to stimulate ECs;and (iv) Inhibition of IL-17 suppresses inflammation. Inhibition of IL-17 with antibodies attenuates vascular inflammation in ApoE-/- mice, suggesting that IL-17 plays a critical role in vascular inflammation. We have a long standing interest in studying immune regulation of endothelial activation and vascular inflammation. Therefore, we have the expertise to complete this project. This goal will be pursued through the execution of the following specific aims: (1) To determine whether IL-17 signaling pathway is upregulated in aortic ECs in ApoE-/- mice;(2) To determine whether IL-17-induced human EC activation is mechanistically dependent on its upregulation of proinflammatory cytokines and chemokines;(3) To determine whether IL-17 gene depletion inhibits EC activation in IL-17-/-/ApoE-/- mice. This project is significant since success of this project may lead to future development of new therapeutics for treating EC activation/inflammation. PUBLIC HEALTH RELEVANCE: There is increasing evidence that vascular endothelial cell (ECs) activation and inflammation significantly contribute to the development of vascular inflammation. However, the importance of newly characterized cytokine interleukin-17 (IL-17) signaling plays a critical role in initiating EC activation and inflammation remains poorly defined. The proposed studies will provide better understanding whether the elucidation of IL-17 molecular signaling in EC activation and inflammation can lead to the development of new therapeutics for treating vascular cell inflammation.